tbuckley/cabot-search huggingface dataset:
Abstract 961: TCF7 promotes a mammary cancer-stem-like phenotype leading to metastasis via potentiation of a hybrid epithelial/mesenchymal (E/M) phenotype
Authors: Huizhi Liang, Outhiriaradjou Benard, Zuen Ren, Kimita Suyama, Larry Norton, Rachel B. Hazan
Journal: Cancer Research (2022)

Abstract Cancer stem cells (CSCs) are a minor population of carcinoma cells that can self-renew and give rise to differentiated progenitors that form the bulk of the tumor. CSCs cause tumor recurrence, chemoresistance and metastasis. The epithelial-to-mesenchymal transition (EMT) promotes tumor cell migration, invasion and cancer stem cell properties. The Wnt signaling pathway is a major driver of cancer stemness and is regulated by the TCF/LEF family of transcription factors. Using loss and gain of function of TCF7 (TCF1) in mouse and human breast cancer cells, we were able to demonstrate that TCF7 promotes cancer stemness through striking regulation of the EMT process. TCF7 knockdown in PyMT mammary tumor cells induced luminal epithelial differentiation, resulting in inhibition of oncosphere formation, migration, tumor growth and lung colonization. However, in keeping with a changing view of EMT as a strictly binary process, we found that TCF7 shifts tumor cells towards a hybrid epithelial/mesenchymal state (E/M) rather than a mesenchymal (M) state. This E/M population was shown to carry stemness and metastatic properties and to be interestingly represented by a small “stem-like” subpopulation in triple negative breast cancer (TNBC) cells. Using CD44 and CD104 (integrin β4) flow cytometry to isolate E/M cells from normal MCF10A and basal-like MDA-MB-468 breast cancer cells, we show that TCF7, Snail, and GSK3β phosphorylation were all highly enriched in this population whereas Zeb-1 (a marker of mesenchymal cells), was absent from E/M cells. These data support a model whereby TCF7 potentiates Wnt signaling which in turn activates GSK3β phosphorylation, resulting in Snail upregulation and enrichment of cells in the E/M state that is conducive of stemness and metastasis. Citation Format: Huizhi Liang, Outhiriaradjou Benard, Zuen Ren, Kimita Suyama, Larry Norton, Rachel B. Hazan. TCF7 promotes a mammary cancer-stem-like phenotype leading to metastasis via potentiation of a hybrid epithelial/mesenchymal (E/M) phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 961.
Abstract 1516: The role of protein tyrosine kinases in DNA mismatch repair
Authors: Hannah Daniels, Breanna Knicely, Eva M. Goellner
Journal: Cancer Research (2022)

Abstract The DNA mismatch repair (MMR) pathway and its regulation are necessary for genomic stability. Cells deficient in MMR exhibit increased expansion and contraction of short repeat sequences in the genome, termed microsatellite instability (MSI). Loss of MMR also results in resistance to certain classes of DNA damaging chemotherapeutics. The standard treatment option for most patients includes chemotherapy, which has toxic side effects. Immunotherapy has recently been utilized as a treatment for various cancers. MSI-high cancers respond better to immunotherapy treatment compared to microsatellite stable (MSS) cancers. This increased response is believed to be due to the higher mutation frequencies associated with the MSI-high tumors, which lead to greater neoantigen production. The primary proteins required for MMR are known, however regulation of the pathway is not well understood. The MLH1 protein is critical for MMR and is required for the excision licensing of the daughter DNA strand. Loss or mutation of MLH1 leads to defective MMR, increased mutation frequency, and MSI. Recent studies by our laboratory and others have shown that treatment with a tyrosine kinase inhibitor, Imatinib, leads to decreased MLH1 protein expression, and resistance to MMR-dependent apoptosis. These observations suggest a link between Imatinib-sensitive protein tyrosine kinases (PTKs) and the regulation of MMR. We show that MLH1 protein reduction is not occurring at the mRNA level and is thought to be post-transcriptional. We have identified the Imatinib sensitive target most likely responsible for the MLH1 reduction phenotype. We show that the target protein and MLH1 have a physical interaction that likely prevents degradation targeting of MLH1 by the Hsp70 chaperone. A detailed understanding of MMR regulation by PTKs would significantly advance the knowledge in the field of MMR and have important implications for immunotherapy strategies. Citation Format: Hannah Daniels, Breanna Knicely, Eva M. Goellner. The role of protein tyrosine kinases in DNA mismatch repair [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1516.
Abstract 245: Interleukin-4 receptor-targeted Abraxane inhibits tumor growth by enhancing drug delivery and reprogramming of M2-type macrophages into M1 phenotype
Authors: Poongkavithai Vadevoo Sri Murugan, Gunassekaran Gowri Rangaswamy, Byungheon Lee
Journal: Cancer Research (2022)

Abstract Abraxane, an albumin-bound paclitaxel nanoparticle, is widely used in treating patients with cancer such as breast cancer. The present study aims at a targeted delivery of Abraxane to tumors by conjugating it with IL4RPep-1, an interleukin-4 receptor (IL4R)-binding peptide. IL4R is up-regulated in many tumor cells and M2-polarized macrophages. IL4R-targeted Abraxane (IL4RPep-1-Abx) showed more efficient binding and internalization into IL4R-high tumor cells and M2-type macrophages than untargeted Abraxane, which was inhibited in part by an inhibitor of macropinocytotsis and receptor-mediated endocytosis, respectively, while being completely inhibited by an IL4R-blocking antibody. In the same context, IL4RPep-1-Abx induced higher levels of cytotoxicity to IL4R-high tumor cells and reprogramming of M2-type macrophages into M1-like phenotype than untargeted Abraxane. In vivo fluorescence imaging showed that IL4RPep-1-Abx homed to tumor, with little accumulation in the liver and lung, more efficiently than untargeted Abraxane. In addition, IL4RPep-1-Abx inhibited tumor growth and metastasis to the lung in 4T1 or LLC tumor-bearing mice and reduced the number of tumor nodules in the lung of K-ras transgenic mice more efficiently than untargeted Abraxane. Liver function was maintained within the normal ranges after treatment with IL4RPep-1-Abx. In 4T1 and LLC tumor tissues, IL4RPep-1-Abx reduced the population of immune-suppressive cells such as M2-type macrophages and increased that of immune-stimulatory cells such as CD8+ T cells compared with untargeted Abraxane. These results suggest that IL4R-targeted Abraxane can enhance the therapeutic efficacy and anti-tumor immunity of Abraxane and is a promising strategy for targeted cancer therapy. Citation Format: Poongkavithai Vadevoo Sri Murugan, Gunassekaran Gowri Rangaswamy, Byungheon Lee. Interleukin-4 receptor-targeted Abraxane inhibits tumor growth by enhancing drug delivery and reprogramming of M2-type macrophages into M1 phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 245.
Abstract 1528: Molecular mechanisms of TSLP as a therapy for CRLF2 B-Cell acute lymphoblastic leukemia
Authors: Hossam Alkashgari, Cornelia Stoian, Caleb Ruiz-Jimenez, Jacqueline Coats, Carlos A. Casiano, Sinisa Dovat, Kimberly J. Payne
Journal: Cancer Research (2022)

Abstract B-cell acute lymphoblastic leukemia (B-ALL) is the most common type of leukemia in children. B-ALL characterized by cytokine receptor-like factor 2 (CRLF2) overexpression (CRLF2 B-ALL) has a survival rate of &amp;lt;30% and is the highest risk sub-group of B-ALL in both adults and children. CRLF2 is a receptor component for the cytokine thymic stromal lymphopoietin (TSLP). TSLP plays a role in the survival and proliferation of B-cell precursors, thus explaining the oncogenic role of increased CRLF2 signaling in CRLF2 B-ALL. To our surprise, we found that high-levels of TSLP eliminated leukemia cells in patient-derived xenograft (PDX) models of CRLF2 B-ALL. CRLF2 and IL-7 receptor-alpha (IL-7Ra) form the heterodimer type-I cytokine receptor for TSLP cytokine. Binding of TSLP to its CRLF2 receptor complex induces JAK-STAT5 and PI3K-AKT pathway signals. TSLP shares the IL-7Ra with Interleukin 7 (IL-7) which has a heterodimer receptor consisting of IL-7Ra and the common gamma chain. High-levels of IL-7 (50 ng/ml) have been shown to induce IL-7Ra internalization and degradation in T-cells. We hypothesize that high-level TSLP induces internalization and degradation of IL-7Ra leading to CRLF2 signal inhibition, death of CRLF2 B-ALL cells and the anti-leukemia effects that we have observed in PDX mice. To test this hypothesis, we treated CRLF2 B-ALL cell lines with different TSLP concentrations to observe the effect of TSLP on its receptor and CRLF2 signaling. Flow cytometry data showed that continuous or a pulse of high-dose TSLP induced a loss of surface IL-7Ra expression for up to 24 hours. Phosphorylation assays showed that cells cultured with high-dose TSLP were unresponsive to subsequent TSLP-induced phosphorylation events (pSTAT5 and pRPS6), indicating CRLF2 signal inhibition. In conclusion, high-dose TSLP induces loss of (IL-7Ra) and inhibition of CRLF2 signaling. These results suggest that TSLP exerts its anti-leukemia effects by shutting down CRLF2-mediated signals possibly via the loss of the IL-7Ra receptor component. Citation Format: Hossam Alkashgari, Cornelia Stoian, Caleb Ruiz-Jimenez, Jacqueline Coats, Carlos A. Casiano, Sinisa Dovat, Kimberly J. Payne. Molecular mechanisms of TSLP as a therapy for CRLF2 B-Cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1528.
Abstract 3871: Solid tumor analytical validation of a T-regulatory immunohistochemistry multiplex for clinical studies
Authors: Marie Gérus-Durand, Elena Baranova, Maroua Tliba, Sabine Iglesias, Manon Motte, Renaud Burrer, Amanda Finan-Marchi
Journal: Cancer Research (2022)

Abstract While classic, chromogenic immunohistochemistry (IHC) remains a mainstay in clinical diagnostics, it can be limiting in the era of immuno-oncology. In the field of immuno-oncology, where access to tissue samples may be limited, there is a need for an accurate interpretation of the sociology and in-depth phenotyping of the cells in the tumor microenvironment that requires a higher level of targets to investigate. Cytotoxic T cells are the main effector cells against tumors. Conversely, T-regulatory cells play a more pro-tumor role by suppressing cytotoxic T cell activation. The importance of the balance and tumor infiltration of these two cell populations has repeatedly been demonstrated in the literature. Due to this, Cerba Research was driven to develop an immunofluorescent multiplex to allow cytotoxic and regulatory T cells detection on the same tissue section for use in solid tumor clinical trials. Following our standard workflow, we developed a CD3-CD8-FoxP3 IHC multiplex (Histoprofile®- T-reg light). This panel allows for analysis of cytotoxic T-cells (CD3+/CD8+/FoxP3-), T helper cells (CD3+/CD8-/FoxP3-) and T regulatory cells (CD3+/CD8-/FoxP3+). Then following our standard process, we performed an analytical validation on a range of formalin fixed paraffin embedded solid tumors (including but not limited to Non Small Cell Lung Cancer, Head and Neck Squamous Cell Carcinoma, Colorectal Cancer and Breast Cancer). Specificity was verified by a pathologist on control tonsil tissue. The robustness of the protocol on a range of solid tumors was verified by the pathologist on tissue blocks and tumor microarrays. Precision tests (intra- and inter-assay) demonstrated a high level of panel reproducibility in solid tumor tissues - CD3 (CV 21.24%), CD8 (CV 19.5%), FoxP3 (CV 13.13%). Using Halo® software (Indica Labs), spatial analysis of the populations of interest can be appreciated in the tumor and stroma compartments. Cerba Research’s Histoprofile®- T-reg light panel passed all the analytical validation criteria for use in clinical studies. Cerba Research can provide this off the shelf panel in solid tumor clinical studies, allowing an elevated analysis of multiple immune biomarkers on a single tissue slide. Citation Format: Marie Gérus-Durand, Elena Baranova, Maroua Tliba, Sabine Iglesias, Manon Motte, Renaud Burrer, Amanda Finan-Marchi. Solid tumor analytical validation of a T-regulatory immunohistochemistry multiplex for clinical studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3871.
Abstract 797: Role of ESR1 mutation in recurrence of tumorigenesis after therapeutic radiation
Authors: S. M. Nashir Udden, Prasanna G. Alluri
Journal: Cancer Research (2022)

Abstract Acquired mutations in ESR1 gene that encodes for Estrogen Receptor (ER) are a common mechanism of acquired resistance to endocrine therapies in breast cancer. However, the role of such mutations in modulation of cell’s response to radiation therapy is poorly understood. In this study, we define the role of ESR1 mutations in altering response to radiation therapy in pre-clinical models of ER-positive breast cancer. To investigate whether ESR1 mutations influence cell’s response to radiation therapy, we employed ER-positive MCF7 and T47D cell lines which have been genome edited to knock-in two of the most common ESR1 mutations, such as Y537S and D538G, found in breast cancer patients. Clonogenic survival assays were carried out to characterize differences in radiation sensitivity of these cells. g-H2AX and Comet assays were employed to study the differences in residual unrepaired DNA damage following radiation in these cell lines. MCF7 cell line-derived xenografts harboring the wild type or mutant ESR1 were employed to study differences in radiation resistance of these tumors in vivo. We found that ER-positive cell lines harboring ESR1 mutations exhibited profound resistance to radiation therapy compared to cell lines harboring the wild type ESR1. These radioresistant cell lines also demonstrated significantly less unrepaired DNA damage following radiation therapy. We observed that mice harboring ESR1 mutant xenografts showed remarkable resistance to radiation therapy. We also observed that ESR1 mutations, which confer resistance to endocrine therapies, also confer profound resistance to radiation therapy. Our findings suggest that oligometastatic ER-positive breast cancer patients who are being treated with radiation therapy (such as those enrolled in NRG BR002 trial) may show significant differences in response to radiation therapy based on their ESR1 mutation status. Recent studies are also exploring the use of neo-adjuvant endocrine therapy in non-metastatic ER-positive breast cancer patients. It is conceivable that some of these patients may acquire ESR1 mutations under selective pressure of neoadjuvant endocrine therapy and may respond poorly to subsequent adjuvant radiation therapy. Overall, our findings support potential personalization of radiation treatments in breast cancer patients based on ESR1 mutation status, heralding an era of precision radiation oncology. Citation Format: S. M. Nashir Udden, Prasanna G. Alluri. Role of ESR1 mutation in recurrence of tumorigenesis after therapeutic radiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 797.
Abstract SY06-03: Development of novel therapeutic strategies to target the DNA damage response in the clinic
Authors: Timothy A. Yap
Journal: Cancer Research (2022)

Abstract The clinical benefit observed with PARP inhibitors, and their subsequent regulatory approval in multiple tumor indications, have provided clinical proof of concept for a synthetic lethal approach in molecularly selected tumors and beyond. Now, we need to build on the success of such first generation PARP inhibitors through the use of rational evidence-based biomarker-driven strategies in the clinic. We can potentially accomplish this through the development of novel potent PARP1-selective inhibitors, which may lead to an improved therapeutic index and patient benefit, and the development of rational PARP inhibitor combinations with other molecularly targeted agents or immunotherapeutics, taking in consideration potential supra-additive toxicities. Finally, given recent advances in drug discovery efforts, we now have the opportunity to go beyond PARP by drugging other key DNA Damage Response (DDR) targets in the clinic, including ATR, WEE1, DNA-PK, RAD51, POLQ and USP1. I will discuss the progress we have made in the clinic, the potential pitfalls, and the promise that such novel approaches hold in improving patient outcomes. Citation Format: Timothy A. Yap. Development of novel therapeutic strategies to target the DNA damage response in the clinic [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY06-03.
Abstract 5300: Therapeutical antibody against TIGIT disrupts inhibitory signaling and restores antitumor immunity
Authors: Hui Zhao, Meng Zhang, Zhengcheng Guo, Cong Zhang, Shuliang Li, Guojin Wu
Journal: Cancer Research (2022)

Abstract T cell immunoglobulin and ITIM domain (TIGIT) is an inhibitory receptor expressed mainly on T cell and NK cells. And because of its central role in limiting antitumor immune response and few immune-related adverse events with defect TIGIT, it has been an attractive target in cancer immunotherapy recently. Here we describe a humanized antibody against TIGIT by blocking its function and mediating ADCC to deplete TIGIT positive Treg cells. The antibody was derived from hybridoma of mice immunized with TIGIT-mFc. Comparing to TIGIT antibody in clinical (Tiragolumab), this antibody had higher affinity to 293T cells overexpressing human TIGIT (EC50=0.45nM vs 1.3nM) or cyno TIGIT (EC50=2.6nM vs 13nM), and also had higher binding affinity to activated CD8 T cell from PBMC (EC50=0.65nM vs 1.47nM), with lower Kd (0.9nM vs 1.8nM). This antibody also more efficiently blocked TIGIT binding to its ligand CD155 overexpressed on 293T cells with FACS assay than Tiragolumab (IC50=1nM vs. 1.4nM). In the cell-based reporter assay, the antibody had a lower IC50 than Tiragolumab (5nM vs. 21nM). When the primary CD8 T cell was co-cultured with 293T cells overexpressing CD155 and anti-CD3 scFv (OKT3) on the surface, the antibody increased the secretion of INF-γ along with an increase of antibody concentration. At last, this antibody-mediated depletion of TIGIT positive Treg from PBMC cultured in vitro with higher efficiency than Tiragolumab. In sum, the antibody described here was a better candidate drug targeting TIGIT for cancer immunotherapy Citation Format: Hui Zhao, Meng Zhang, Zhengcheng Guo, Cong Zhang, Shuliang Li, Guojin Wu. Therapeutical antibody against TIGIT disrupts inhibitory signaling and restores antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5300.
Abstract 2167: Machine learning-based tissue of origin classification for cancer of unknown primary diagnostics using genome-wide mutation features
Authors: Luan Nguyen, Luuk Schipper, Paul Roepman, Kim Monkhorst, Arne van Hoeck, Petur Snaebjornsson, Edwin Cuppen
Journal: Cancer Research (2022)

Abstract Tumor tissue of origin (TOO) is an important factor for guiding treatment decisions. However, TOO cannot be determined for ~3% of metastatic cancer patients that present in the clinic and are categorized as cancers of unknown primary (CUP). As whole genome sequencing (WGS) of tumors is now transitioning from the research domain to diagnostic practice in order to address the increasing demand for biomarker detection, its use for detection of TOO in routine diagnostics also starts becoming within reach. While proof of concept for the use of genome-wide features has been demonstrated before, more complex WGS mutation features, including structural variant (SV) driver and passenger events, have never been integrated into TOO-classifiers even though they bear highly characteristic links with tumor TOO. Using a uniformly processed dataset containing 6820 whole-genome sequenced primary and metastatic tumors (ICGC/PCAWG and Hartwig cohors), we have developed Cancer of Unknown Primary Location Resolver (CUPLR), a random forest based TOO classifier that employs 502 genome-wide features based on simple and complex somatic driver and passenger mutations. Our model is able to distinguish 33 cancer (sub)types with an overall accuracy of 91% and 89% based on cross-validation (n=6139) and hold out set (n=681) predictions, respectively. We found that SV derived features increase the accuracy and utility of TOO classification for specific cancer types. To ensure that predictions are human-interpretable and suited for use in routine diagnostics, CUPLR reports the top contributing features and their values compared to cohort averages. The comprehensive output of CUPLR is complementary to existing histopathological procedures and may thus improve diagnostics for patients with CUP. CUP is the first reimbursed indication for WGS in The Netherlands. We will report on the prospective use and clinical utility of WGS for CUP patients in routine diagnostics but also highlight the added value of CUPLR for unsolved differential diagnosis cases and incidental cases where the independent WGS analysis was discrepant with the original tumor diagnosis. Citation Format: Luan Nguyen, Luuk Schipper, Paul Roepman, Kim Monkhorst, Arne van Hoeck, Petur Snaebjornsson, Edwin Cuppen. Machine learning-based tissue of origin classification for cancer of unknown primary diagnostics using genome-wide mutation features [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2167.